Lipoprotein lipase is the critical enzyme responsible for the hydrolysis of triglyceride-rich lipoproteins in the peripheral circulation. Cells, such as cardiac and skeletal myocytes, macrophages, and adipocytes synthesize and secrete lipoprotein lipase. It then traverses the basement membrane separating these cells from the microvasculature in the tissue. The enzyme is transported across the endothelial cells to its site of action on the lumen of the endothelium. Evidence suggests that transport depends on lipoprotein lipase binding to heparan sulfate proteoglycans. However, these studies were done in aortic endothelial cells, which are not physiologically relevant, and the identification of the active heparan sulfate proteoglycans was not determined. We hypothesize that specific heparan sulfate proteoglycans drive the transport of lipoprotein lipase from the abluminal side of the endothelium to its site of action on the luminal side. We intend to test this hypothesis through three specific aims: First, we will identify the relevant cardiac endothelial cell heparan sulfate proteoglycans that interact with lipoprotein lipase. Next, we will test if lipoprotein lipase transport across cardiac endothelial cells depends on heparan sulfate proteoglycans. Finally, we will test if lipoprotein lipase utilizes heparan sulfate proteoglycans for transport in vivo using mice bearing mutations in heparan sulfate biosynthesis or proteoglycan core proteins. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death in the United States. Impairments in the expression, transport, or function of lipoprotein lipase can lead to hypertriglyceridemia, atherosclerosis, and other cardiovascular diseases. These studies will better define the role of heparan sulfate proteoglycans In the trafficking of lipoprotein lipase and will provide insight into the consequences of impaired heparan sulfate proteoglycan- lipoprotein lipase interactions in vivo.